“Biosimilars will provide access to important therapies for patients who need them,” FDA Commissioner Margaret A. Hamburg, MD, said in a statement. “Patients and the healthcare community can be confident that biosimilar products approved by the FDA meet the agency’s rigorous safety, efficacy, and quality standards.”

Zarxio was unanimously recommended for approval in early-January by the FDA's ODAC panel. The drug, which is being developed by Sandoz Biopharmaceuticals, a unit of Novartis, is manufactured using recombinant technology in E. coli host cells. The production process involves various steps that isolate and purify met-C-GSF. The drug is produced in pre-filled syringes and at the same strengths (300 mcg/0.5 ml and 480 mcg/0.8 ml) as Neupogen.

"Filgrastim has proven clinical value in treating patients at increased risk of neutropenia, but it is underused in the US for a variety of reasons, including price," Louis Weiner, MD, chairman of the department of Oncology and director of the Lombardi Comprehensive Cancer Center at Georgetown University, said in a statement. "Biosimilars have the potential to increase access and the approval of Zarxio may reduce costs to the healthcare system. The comprehensive data set supports its use in clinical practice."

Zarxio was the first drug to be reviewed under the US biosimilar pathway established under the Affordable Care Act. US law defines biosimilars as biological products demonstrated to be “interchangeable” with an FDA-licensed biological product.

The FDA based its approval of Zarxio on data Sandoz submitted from five pharmacokinetic/pharmacodynamics studies, five nonclinical studies, and two clinical studies.

Sandoz used European Union (EU)-approved Neupogen as a comparator in some of these studies, and thus the FDA required that the company establish the biosimilarity of US-licensed Neupogen, (EU)–approved Neupogen, and EP2006. The FDA determined that through pair-wise comparisons of the three products, Sandoz established an adequate “bridge” showing that the treatments met the predetermined criteria for analytical similarity.

Among all the data Sandoz submitted, the key clinical study the FDA based its approval on was the pivotal double-blind phase III PIONEER trial (EP06-302), which compared the efficacy and safety of Zarxio and US-licensed Neupogen in patients with breast cancer treated with myelosuppressive chemotherapy. In the study submitted to the FDA, all patients received six cycles of TAC chemotherapy (taxotere at 75 mg/m2 IV, adriamycin at 50 mg/m2 IV, and cytoxan at 500 mg/m2 on day 1 of each 21-day cycle) and were randomized to either six cycles of EP2006, six cycles of filgrastim, or one of two six-cycle regimens that rotated between the two drugs.

Neupogen or Zarxio were administered subcutaneously at 5 mcg/kg body weight starting on day 2 of cycle 1 and given until the absolute neutrophil count (ANC) recovered to 10 Gi/L after the nadir or a maximum of 14 days, whichever came first.

The primary endpoint was duration of severe neutropenia (DSN), which the researchers defined as the number of consecutive days a patient’s ANC was <0.5 Gi/L after the first cycle of chemotherapy. For this analysis, which included 204 patients, the researchers combined all patients who received Zarxio (N = 101) in the first cycle and compared them with all patients who received filgrastim (N = 103) in the first cycle.

The results showed that the study met its primary endpoint, with a cycle 1 mean DSN of 1.17 and 1.20 days, respectively, for patients receiving Zarxio and filgrastim. The filgrastim minus Zarxio DSN difference was 0.04 days (90% CI, -0.21-0.28). The mean time to absolute neutrophil count recovery in cycle 1 was 1.8 days ± 0.97 in the Zarxio arm compared with 1.7 days ± 0.81 in the filgrastim arm.

The data also showed that repeated switching at each cycle between the investigational biosimilar and Neupogen had no impact on efficacy, safety or immunogenicity. There were no significant adverse event differences.

In pharmacokinetic/pharmacodynamics studies, both Zarxio and Neupogen were found to have similar activity, when looking at the area under the curve (AUC) and peak serum concentration (Cmax). Following a single dose of either drug, the AUC and Cmax were within 80% to 125%, with a 90% confidence interval. Absolute neutrophil counts and CD34+ cell counts were within 80% and 125% of each other, following treatment (95% CI).

"The FDA approval of Zarxio marks a significant milestone for the United States healthcare system and for patients who might suffer from neutropenia," Carol Lynch, global head of Biopharmaceuticals & Oncology Injectables at Sandoz, said in a statement. "As the global leader in biosimilars, we are honored to be the first company to successfully work with FDA to navigate the US biosimilar pathway and we look forward to making this high-quality biosimilar available to patients in the US."